Model of Hypercortisolism for Major Depression

重度抑郁症的皮质醇增多症模型

基本信息

批准号：
7096240
负责人：
ALAN F. SCHATZBERG
金额：
$ 62.3万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-30 至 2011-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The proposed research continues previously funded studies of behavioral, cellular, and molecular genetic aspects of hypothalamic-pituitary-adrenal (HPA)-axis regulation and post-stress recovery. The central hypothesis is that diminished hippocampal volume is a cause and not just an effect of stress-related psychopathology as modeled in adult female monkeys. Female animal models of stress-related depressive disorders are important because prevalence rates of depression in women are nearly two-times higher than in men. There is also a need to bridge the gap between brain imaging studies of humans with major depression and animal models that focus on cellular and molecular levels of neuroscience research. In this regard, nonhuman primates offer attractive opportunities for cross-disciplinary translational research. The studies proposed here test in monkeys the following specific predictions. Adult females with small hippocampal volumes (i.e., selected from the bottom third of a normal distribution) determined before initiation of the study will respond to repeated exposure to cycles of social isolation-induced hypercortisolism with impaired spatial memory, increased anhedonia, and HPA-axis dysregulation as compared to females with large hippocampi (i.e., top third of the distribution) exposed to cycles of social isolation, or matched female monkey controls housed continuously in pairs. In response to subsequent social stimulation after each cycle of social isolation, females with small hippocampi will show an impaired capacity for recovery. Females exposed to cycles of isolation and social stimulation will also exhibit hippocampal volume loss as compared to matched female controls housed continuously in pairs. The behavioral and neuroendocrine effects of hippocampal atrophy will be greatest in females with initially small hippocampal volumes as predicted by a threshold model described in the Research Plan. Adult females with initially small hippocampi will respond to repeated isolation and social stimulation with diminished hippocampal neurogenesis and increased glucocorticoid receptor gene expression compared to females with equally small hippocampi housed in stable pairs. These studies cross the boundaries of molecular, cellular, and behavioral neuroscience with the ultimate goal of building a foundation for improved treatments and the prevention of major depression by elucidating the relationship between hypercortisolism and hippocampal volume.

描述（由申请人提供）：拟议的研究继续对下丘脑 - 垂体 - 肾上腺（HPA）轴轴调节和应激后恢复的行为，细胞和分子遗传方面进行了先前资助的研究。中心假设是，海马体积减少是一个原因，而不仅仅是与压力相关的精神病理学的作用，正如成年雌性猴子所建立的那样。与压力有关的抑郁症的女性动物模型很重要，因为女性的抑郁症患病率几乎比男性高两次。还需要弥合患有重大抑郁症的人类大脑成像研究与侧重于细胞和分子神经科学研究水平的人的差距。在这方面，非人类灵长类动物为跨学科翻译研究提供了有吸引力的机会。这里提出的研究在猴子中测试以下特定预测。在开始研究之前确定的具有海马体积较小的成年女性（即，从正态分布的底部中选择）将响应反复暴露于社会隔离引起的周期的循环，并在空间记忆下，空间记忆受损，Anhedonia和Anhedonia和HPA-avesis的分布与大型HPA的分布（I. cy cy in I. cyepycy of Hippocococip）（I.社会隔离，或匹配的雌性猴子对照组合成对持续容纳。为了应对每个社会隔离周期后随后的社会刺激，海马小的女性将显示康复能力受损。与匹配的女性对照组相比，接触到隔离和社交刺激周期的女性也会表现出海马体积损失。如研究计划中描述的阈值模型所预测的那样，海马萎缩的行为和神经内分泌作用将是最初具有较小海马体积的女性中最大的。与在稳定对中同样小的海马相比，海马神经发生的反复分离和社交刺激的反复隔离和社交刺激的反应增加，糖皮质激素受体基因表达增加，与稳定对同样小的海马相比，糖皮质激素受体基因表达增加。这些研究跨越了分子，细胞和行为神经科学的边界，最终目标是通过阐明高皮层溶质和海马体积之间的关系来改善治疗和预防重大抑郁症的基础。